Gastrokine 1 mRNA in human sera is not informative biomarker for gastric cancer

Gastric cancer (GC) is still one of the prevalent leading causes of cancer-related deaths worldwide and high mortality rate is mainly due to late-stage diagnosis [2]. Survival rate at 5 years of about 20 % in most areas of the world [6, 11, 32], except in Japan where mass screening programs, staging systems, and treatment may contribute to superior 5-year survival rates of approximately 60 % [30, 35, 37]. In all Europe, the incidence is about 104,620 and 69,394 among males and females, respectively [16], representing about 23 % of all cancers.

The most common type of stomach cancer is adenocarcinoma, which is divided into intestinal (well-differentiated) and diffuse (undifferentiated) each having different epidemiological and pathophysiological features [20]. The intestinal-type generally evolves through a relatively well-defined sequence of histological lesions, namely non-atrophic gastritis, chronic atrophic gastritis, intestinal metaplasia, and dysplasia [4, 5]. On the contrary, the diffuse-type has instead a poorer prognosis and develops through unknown genetic and morphological events from normal gastric epithelium. The pathogenesis of GC remains poorly understood however several environmental factors, such as Helicobacter pylori (H. pylori) infection can be the cause leading to this disease. This risk is probably the result of a combination of genetic and environmental factors in which the infection by H. pylori is of particular relevance.

In a previous work, we analyzed the protein profile of malignant and normal gastric tissues and identified a novel stomach specific protein gastrokine 1 (GKN1) whose expression was reduced in H. pylori infected gastric mucosa and down-regulated or completely absent in GC tissues and precancerous lesions. [13, 28]. GKN1 belongs to a family of genes encoding stomach-specific proteins formed by 3 known members: GKN1 [23], GKN2 [9], and GKN3 [26]. These proteins, besides a highly conserved structure, show convergent functions in terms of modulation of gastric mucosal homeostasis and inflammation, activity in epithelial wound healing and/or repair, and anti-proliferative activity. Moreover, they are highly expressed in the normal stomach and loss of GKNs expression in gastric cancers suggests putative tumor suppressor roles [24]. For instance, GKN2 knockout mice showed defective gastric epithelial differentiation whereas, loss of GKN2 in gp130F/F caused tumorigenesis of the proximal stomach. Furthermore, in H. pylori–infected GKN2 knockout mice, gastric immunopathology was accelerated and associated with augmented T helper cell type 1 (Th1) [25]. However, GKNs modes of action remain unsolved. Some findings indicated the involvement of GKN1 in the replenishment of the surface lumen epithelial cell layer, and in maintaining mucosal integrity [36]. After injury of the gastric mucosa, restoration may occur very rapidly in the presence of GKN1. In contrast, if the protein is down-regulated the repair process may be hampered [19]. Application of GKN1 to gastrointestinal cells promoted epithelial restoration and exerted its protective effect by increasing accumulation of specific tight and adherens junction proteins and also protecting their loss after injury [33].

Under this consideration, GKN1 might represent an important biomarker in carcinogenic process since it was seen that individuals with a lower expression of the protein have an increased risk to develop gastric diseases. We hypothesized that GKN1 mRNAs identified in serum of GC patients could become a completely non-invasive biomarker potentially distinguishing GC patients from healthy individuals.